Beta thalassemia (β-thalassemia) syndromes are a heterogeneous group of inherited hemoglobinopathies caused by molecular defects in the beta-globin gene that lead to the impaired synthesis of beta-globin chains of the hemoglobin. The hallmarks of the disease include ineffective erythropoiesis, chronic hemolytic anemia, and iron overload. Clinical presentation ranges from asymptomatic carriers to severe anemia requiring lifelong blood transfusions with subsequent devastating complications. The management of patients with severe β-thalassemia represents a global health problem, particularly in low-income countries. Until recently, management strategies were limited to regular transfusions and iron chelation therapy, with allogeneic hematopoietic stem cell transplantation available only for a subset of patients. Better understanding of the underlying pathophysiological mechanisms of β-thalassemia syndromes and associated clinical phenotypes has paved the way for novel therapeutic options, including pharmacologic enhancers of effective erythropoiesis and gene therapy.

Before the advent of effective iron chelation, death from iron-induced cardiomyopathy and endocrine failure occurred in the second decade in patients with thalassemia major, and this experience has driven expectation of poor outcomes and caused anxiety in all disorders associated with iron loading to this day. To be clear, severe iron overload still causes significant morbidity and mortality in many parts of the world, but current understanding of iron metabolism, noninvasive monitoring of organ-specific iron loading in humans, and effective iron chelators have dramatically reduced morbidity of iron overload. Furthermore, clinical experience in hemoglobinopathies supports iron biology learned from animal studies and identifies common concepts in the biology of iron toxicity that inform the management of iron toxicity in several human disorders. The resultant significant increase in survival uncovers new complications due to much longer exposure to anemia and to iron, which must be considered in long-term therapeutic strategies. This review will discuss the management of iron toxicity in patients with hemoglobinopathies and transfusion-dependent anemias and how iron biology informs the clinical approach to treatment.

The effect of pretransfusion hemoglobin on transfusion burden, thrombosis, and mortality in thalassemia and myelodysplastic syndrome is unclear. We aimed to study the pretransfusion hemoglobin and erythrocyte transfusion burden and investigate the effects of these variables on each other in real-life in thalassemia and myelodysplastic syndrome. Adult patients with thalassemia and myelodysplastic syndrome who received at least one erythrocyte concentrate unit outpatient at Sanliurfa Mehmet Akif Inan Training and Research Hospital during 1 year were included in the study. The data were retrospectively obtained. Ethical approval was obtained for the study. Ninety-two patients were included in the study. In thalassemia major, pretransfusion hemoglobin ≥ 9 g/dL was associated with a lower median annual number of transfused erythrocyte concentrate units (15 vs. 27) and median annual number of transfusion sessions (11 vs. 14) p=0.002, p=0.009, respectively). In myelodysplastic syndrome, a pretransfusion hemoglobin level ≥ 8 g/dL was associated with a lower median annual number of transfused erythrocyte concentrate units (6 vs. 24) (p=0.016). In thalassemia major with an intact spleen, pretransfusion hemoglobin ≥ 8 g/dL was associated with an increased median annual number of transfused erythrocyte concentrate units (32 vs. 27) and median annual number of transfusion sessions (18 vs. 14) (p=0.046, p=0.038, respectively). In conclusion, higher pretransfusion hemoglobin levels were related to a lower transfusion burden in thalassemia major and myelodysplastic syndrome.

Beta (β)-thalassemia and sickle cell disease (SCD) are characterized by a hypercoagulable state, which can significantly influence organ complication and disease severity. While red blood cells (RBCs) and erythroblasts continue to play a central role in the pathogenesis of thrombosis in β-thalassemia and SCD, additional factors such as free heme, inflammatory vasculopathy, splenectomy, among other factors further contribute to the complexity of thrombotic risk. Thus, understanding the role of the numerous factors driving this hypercoagulable state will enable healthcare practitioners to enhance preventive and treatment strategies and develop novel therapies for the future. We herein describe the pathogenesis of thrombosis in patients with β-thalassemia and SCD. We also identify common mechanisms underlying the procoagulant profile of hemoglobinopathies translating into thrombotic events. Finally, we review the currently available prevention and clinical management of thrombosis in these patient populations.

Patients with β-thalassemia continue to have several unmet needs. In non-transfusion-dependent patients, untreated ineffective erythropoiesis and anemia have been associated with a variety of clinical sequelae, with no treatment currently available beyond supportive transfusions. In transfusion-dependent forms, lifelong transfusion and iron chelation therapy are associated with considerable clinical, psychological, and economic burden on the patient and health care system. Luspatercept is a novel disease-modifying agent targeting ineffective erythropoiesis that became recently available for patients with β-thalassemia. Data from randomized clinical trials confirmed its efficacy and safety in reducing transfusion burden in transfusion-dependent patients and increasing total hemoglobin level in non-transfusion-dependent patients. Secondary clinical benefits in patient-reported outcomes and iron overload were also observed on long-term therapy, and further data from real-world evidence studies are awaited.

Iron, an essential mineral in the body, is involved in numerous physiological processes, making the maintenance of iron homeostasis crucial for overall health. Both iron overload and deficiency can cause various disorders and human diseases. Ferroptosis, a form of cell death dependent on iron, is characterized by the extensive peroxidation of lipids. Unlike other kinds of classical unprogrammed cell death, ferroptosis is primarily linked to disruptions in iron metabolism, lipid peroxidation, and antioxidant system imbalance. Ferroptosis is regulated through transcription, translation, and post-translational modifications, which affect cellular sensitivity to ferroptosis. Over the past decade or so, numerous diseases have been linked to ferroptosis as part of their etiology, including cancers, metabolic disorders, autoimmune diseases, central nervous system diseases, cardiovascular diseases, and musculoskeletal diseases. Ferroptosis-related proteins have become attractive targets for many major human diseases that are currently incurable, and some ferroptosis regulators have shown therapeutic effects in clinical trials although further validation of their clinical potential is needed. Therefore, in-depth analysis of ferroptosis and its potential molecular mechanisms in human diseases may offer additional strategies for clinical prevention and treatment. In this review, we discuss the physiological significance of iron homeostasis in the body, the potential contribution of ferroptosis to the etiology and development of human diseases, along with the evidence supporting targeting ferroptosis as a therapeutic approach. Importantly, we evaluate recent potential therapeutic targets and promising interventions, providing guidance for future targeted treatment therapies against human diseases.

Ineffective erythropoiesis and subsequent anemia as well as primary and secondary (transfusional) iron overload are key drivers for morbidity and mortality outcomes in patients with β-thalassemia.

In this review, we highlight evidence from observational studies evaluating the association between measures of anemia and iron overload versus outcomes in both non-transfusion-dependent and transfusion-dependent forms of β-thalassemia.

Several prognostic thresholds have been identified with implications for patient management. These have also formed the basis for the design of novel therapy clinical trials by informing eligibility and target endpoints. Still, several data gaps persist in view of the challenge of assessing prospective long-term outcomes in a chronic disease. Pooling insights on the prognostic value of different measures of disease mechanism will be key to design future scoring systems that can help optimize patient management.

Advances in understanding the disease process in β-thalassemia supported development of various treatment strategies that resulted in improved survival. Improved survival, however, allowed multiple morbidities to manifest and cemented the need for frequent, lifelong treatment. This has directly impacted patients' health-related quality of life and opened the door for various psychiatric and cognitive disorders to potentially develop. In this review, we summarize available evidence on quality of life, depression and anxiety, suicidality, and cognitive impairment in adult patients with β-thalassemia while sharing our personal insights from experience in treating patients with both transfusion-dependent and non-transfusion-dependent forms.

The increase in the number of patients with hemoglobinopathies in Europe in recent decades highlights the need for more detailed epidemiological information in Spain. To fulfil this need, the Spanish Society of Pediatric Hematology and Oncology (SEHOP) sponsored the creation of a national registry of hemoglobinopathies known as REHem-AR (Spanish Registry of Hemoglobinopathies and Rare Anemias). Data from the transfusion-dependent (TDT) and non-transfusion-dependent (NTDT) β-thalassemia cohorts are described and analyzed.

We performed an observational, multicenter, and ambispective study, which included patients of any age with TDT and NTDT, registered up to December 31, 2021.

Among the 1741 patients included, 168 cases of thalassemia were identified (103 TDT and 65 NTDT-patients). Survival at 18 years was 93% for TDT and 100% for NTDT. Regarding management, 80 patients with TDT (77.7%) and 23 patients with NTDT (35.4%) started chelation treatment during follow-up, with deferasirox being the most widely used. A total of 76 patients within the TDT cohort presented at least 1 complication (73.8%), the most frequent being hemosiderosis and osteopenia-osteoporosis. Comparison of both cohorts revealed significant differences in the diagnosis of hepatic hemosiderosis (p = 0.00024), although these were not observed in the case of cardiac iron overload (p = 0.27).

Our registry enabled us to describe the management of β thalassemia in Spain and to analyze the morbidity and mortality of the cohorts of patients with TDT and NTDT. Complications related to iron overload in TDT and NTDT account for most of the morbidity and mortality of the disease, which is associated with a considerable social, psychological, and economic impact, although cardiac, osteopathy and endocrinological complications requiring more attention. The convenience and simplicity of online registries make it possible to homogenize variables and periodically update data, thus providing valuable information on these diseases.

Compound heterozygotes for deletional β-thalassemia can be difficult to diagnose due to its diverse clinical presentations and no routine screenings. This can lead to disease progression and delay in treatment.

We reported pedigree analysis and genetic research in a family with rare β-thalassemia.

Pedigree analysis and genetic research demonstrated that the patient was a compound heterozygote for β-thalassemia CD17/Southeast Asian hereditary persistence of fetal hemoglobin deletion, inherited from the parents. Magnetic resonance imaging T2* examination revealed severe iron deposition in the liver. Echocardiography revealed endocardial cushion defect.

The patient was treated with Deferasirox after receiving the final molecular genetic diagnosis. The initial once-daily dose of Deferasirox was 20 mg/kg/d.

The patient discontinued the medication three months after the first visit. Two years later, the patient visited the Department of Hepatobiliary and Pancreatic Diseases. He was recommended to undergo splenectomy after surgical repair of the congenital heart disease. However, the patient refused surgical treatment because of the economic burden.

We report that fetal hemoglobin is a sensitive indicator for screening large deletions of the β-globin gene, which can be effectively confirmed by the multiplex ligation-dependent probe amplification assay. In non-transfusion-dependent thalassemia patients, iron status assessment should be regularly performed, and iron chelation treatment should be initiated early. This case will provide insights for the diagnosis of rare genotypes of β-thalassemia and has important implications for genetic counseling.